Phenylketonuria (PKU) is a genetic disorder of metabolism characterized by a pathological elevation of phenylalanine (Phe) in the body stemming from a dysfunctional phenylalanine hydroxylase enzyme (PAH). The resulting high concentrations of Phe (5-10x) can result in severe intellectual disability, behavioral problems, and neurological deficits (e.g. seizures). Strict control of dietary Phe is the primary treatment for PKU current guidelines require diet therapy to be continued for life, which markedly exacerbates the problem of non-compliance, especially in older children and adults. An alternative treatment for PKU involves the ?replacement? of the endogenous PAH with a different Phe metabolizing enzyme such as phenylalanine ammonia lyase (PAL). Orally administered PAL reduced plasma Phe levels, but this effect was transient as the destruction of PAL by harsh environment of the gastrointestinal tract (g.i.t) necessitated huge doses of the enzyme. We have designed a novel technology to reduce dietary Phe levels in the g.i.t. by oral administration of microencapsulated PAL. Preliminary studies have demonstrated that we can successfully encapsulate PAL (PALE) in ethyl cellulose using a patented emulsion-dispersion technique. However, PALE exhibits ~30% of the activity of unencapsulated enzyme (PALU) in solution limiting its implementation in its current form. The goal of this proposal is to optimize the formulation parameters to encapsulate PAL and characterize its properties in vitro enabling future development efforts.